Introduction

Cardiovascular disease (CVD) complicates 0.2–4% of all pregnancies in the Western world . It remains the leading cause of maternal death in many developed countries, including the UK .

Data from the Centre for Maternal and Child Enquiries (CMACE) have shown that the numbers of women dying from cardiac disease has increased from 7.3 per million maternities in the 1982–1984 triennium, to 23.1 per million maternities in the 2006–2008 triennium . Fifty-three maternal deaths from cardiac disease occurred between 2006 and 2008. The leading cardiac causes were found to be sudden adult death syndrome, myocardial infarction, dissection of the thoracic aorta, and cardiomyopathy, most commonly peripartum cardiomyopathy. It is important not to forget that the numbers of pregnant women who have had corrective or palliative surgery for congenital cardiac diseases, and those who have had pacemakers or prosthetic heart valves fitted, is increasing. In addition, the incidence of acquired heart disease is increasing because of older age at first pregnancy and a higher prevalence of cardiovascular risk factors, such as hypertension, diabetes and obesity.

Significant cardiovascular changes occur in pregnancy from an early gestation . This can affect the types and doses of drugs used in pregnancy. Peripheral vasodilatation, probably related to progesterone, is the primary event that leads to a fall in the systemic vascular resistance, and, to compensate for this, cardiac output increases by 40% during pregnancy. The heart can increase in size by up to 30%. Pregnancy induces a series of haemostatic changes, with an increase in coagulation factors, fibrinogen, and platelet adhesiveness, as well as reduced fibrinolysis. This leads to a hypercoagulable state and an increased risk of venous thromboembolism. Also, venous return is obstructed by the enlarging gravid uterus, causing stasis and a further increase in thrombosis risk.

Physiological changes that occur during pregnancy can affect absorption, excretion, and bioavailability of all drugs . Higher dosages of drugs may be required to achieve therapeutic plasma concentrations. This is partly explained by the increased intravascular blood volume. In addition, the raised renal perfusion and the higher hepatic metabolism increase drug clearance. The altered pharmacokinetics of drugs vary in magnitude during different stages of pregnancy, making careful monitoring of the patient and dose adjustments necessary.

Many different factors have to be taken into account when prescribing a drug to a pregnant woman. These factors include the gestational age of the fetus, route of drug administration, whether and how effectively the drug crosses the placenta, and the necessary effective dose of the drug . Awareness of the unique physiological changes of pregnancy that affect the pharmacokinetics of medications used by pregnant women is of paramount importance in deciding the dosage and frequency of administration and monitoring. A major concern is the potential harm to the fetus but, perhaps more importantly, is the assessment of potential harm to the mother from withholding a drug or using an insufficient dose. The question of whether the benefits outweigh the risks has to be asked in each individual case.

Cardiac disease in pregnancy encompasses a breadth of conditions, ranging from disease causing only minor concern, to conditions associated with significantly increased risks of maternal morbidity and mortality . In this chapter, we will discuss the use of drug treatment in pregnant women with congenital, as well as in those with acquired, cardiac disease. We will start by discussing the forms of contraception that may be appropriate to use. We will then discuss drugs specifically used to treat cardiac conditions in pregnant woman and their effect on the pregnancy. Finally, we will discuss the potential adverse effects of obstetric-specific drugs that act on the uterus, specifically uterotonics and tocolytics, when used in women with cardiac disease.

Contraception

All women with cardiac disease should be given advice about adequate contraception, so that informed choices about potential future pregnancies can be made. Pre-conception counselling is often invaluable to optimise the cardiac condition before pregnancy to ensure current drug treatment is compatible with pregnancy and to gain access to healthcare professionals who have expertise in managing women with cardiac disease in pregnancy. The Royal College of Obstetricians and Gynaecologists recommends that teenage girls, in particular, with congenital heart disease should have access to specialists who can advise on contraception and pregnancy .

It is important to disseminate accurate information about contraception to all healthcare professionals responsible for looking after women with cardiac disease. This is mainly to avoid unplanned pregnancies in women for whom pregnancy carries an extremely high risk of maternal mortality, and to avoid inaccurate advice to terminate the pregnancy in women whose cardiac risk associated with pregnancy is low.

A number of important factors must be considered when deciding upon the best form of contraception in women with heart disease. These include the risk of pregnancy for the woman, the effect of the contraceptive method on her cardiac disease, the failure rates associated with the contraceptive method, the consequences of an unplanned pregnancy, and the compliance and preferences of the individual woman.

The UK Medical Eligibility Criteria for contraceptive use (UKMEC) are a useful guide for women on their contraceptive options based on their medical condition. Four categories exist, ranging from category 1, where there is no restriction on the use of the contraceptive method, to category 4 where the condition represents an unacceptable health risk if the contraceptive method is used. For women who have more complex cardiac conditions, however, a multidisciplinary meeting involving cardiologists and sexual and reproductive health specialists is advised. The decision about contraception should be based on a risk–benefit analysis of the contraceptive method. The individual’s risks of the contraceptive method adversely affecting her medical condition should be balanced against the risks of an unwanted pregnancy and its subsequent health implications for the woman.

Contraception

All women with cardiac disease should be given advice about adequate contraception, so that informed choices about potential future pregnancies can be made. Pre-conception counselling is often invaluable to optimise the cardiac condition before pregnancy to ensure current drug treatment is compatible with pregnancy and to gain access to healthcare professionals who have expertise in managing women with cardiac disease in pregnancy. The Royal College of Obstetricians and Gynaecologists recommends that teenage girls, in particular, with congenital heart disease should have access to specialists who can advise on contraception and pregnancy .

It is important to disseminate accurate information about contraception to all healthcare professionals responsible for looking after women with cardiac disease. This is mainly to avoid unplanned pregnancies in women for whom pregnancy carries an extremely high risk of maternal mortality, and to avoid inaccurate advice to terminate the pregnancy in women whose cardiac risk associated with pregnancy is low.

A number of important factors must be considered when deciding upon the best form of contraception in women with heart disease. These include the risk of pregnancy for the woman, the effect of the contraceptive method on her cardiac disease, the failure rates associated with the contraceptive method, the consequences of an unplanned pregnancy, and the compliance and preferences of the individual woman.

The UK Medical Eligibility Criteria for contraceptive use (UKMEC) are a useful guide for women on their contraceptive options based on their medical condition. Four categories exist, ranging from category 1, where there is no restriction on the use of the contraceptive method, to category 4 where the condition represents an unacceptable health risk if the contraceptive method is used. For women who have more complex cardiac conditions, however, a multidisciplinary meeting involving cardiologists and sexual and reproductive health specialists is advised. The decision about contraception should be based on a risk–benefit analysis of the contraceptive method. The individual’s risks of the contraceptive method adversely affecting her medical condition should be balanced against the risks of an unwanted pregnancy and its subsequent health implications for the woman.

Combined oestrogen–progesterone contraception

Combined oestrogen–progesterone contraception includes the combined oral contraceptive pill, the combined transdermal patch, and the combined vaginal ring.

The oestrogen component carries an increased thrombotic risk owing to an increase in the circulating Vitamin K-dependent clotting factors, an increase in plasminogen, a decrease in anti-thrombin, and an increase in platelet adhesion. An increase in circulating volume causes the risk of hypertension to increase, and dyslipidaemia may worsen .

Combined hormonal contraceptives should be avoided in women with a history of thromboembolic disease, regardless of their cardiac history. Combined contraceptives containing levonorgestrel may carry a slightly lower risk of thromboembolic disease compared with other combined hormonal contraceptives .

Combined hormonal contraceptives are associated with an increased risk of hypertension (risk ratio of 1.8), especially in women who have used them for more than 5 years . Normotensive women who do not smoke have a small absolute increased risk of ischaemic stroke, and combined oral contraceptives are contraindicated in women with ischemic heart disease, as there is a dose-related increased risk of myocardial infarction (odds ratio of 2.5) . This risk increases almost 10-fold in women who are hypertensive, smoke, or have hyperlipidaemia . Because of the thrombotic risk, combined oral contraceptives are contraindicated in women with pulmonary hypertension . They should also be avoided in women with uncontrolled hypertension.

Progestogen-only contraception

Progestogens cause no significant changes in blood pressure, thrombotic risk or lipid profile, and are therefore suitable for most women with cardiac disease. Progestogen-only oral contraceptives, however, have a higher failure rate than combined hormonal contraceptives. The contraceptive effect relies on strict patient compliance, as etynodiol, norethisterone, and levonorgestrel must be taken within the same 3-h window each day to maintain contraceptive protection. Unlike other progestogen-only oral contraceptives, desogestrel inhibits ovulation in most women, and the missed pill window is extended to 12 h. Desogestrel (Cerazette ^® ) may therefore benefit women who are suitable for progestogen-only contraception but have difficulty with compliance.

Women with pulmonary arterial hypertension receiving bosentan need an increased dose of desogestrel, as bosentan induces the cytochrome P450 enzymes CYP2C9 and CYP3A4. They should also be advised to use a supplementary form of contraception, such as condoms, as the risks associated with contraceptive failure in women with pulmonary hypertension are extremely serious . Emergency hormonal contraception is safe after unprotected intercourse in women with pulmonary arterial hypertension. Progestogen-only contraception is a suitable form of contraception for women on long-term anticoagulation therapy, for example those with metallic prosthetic cardiac valves.

Intrauterine contraception

The copper-releasing intrauterine device (IUD) works by inhibiting fertilisation, as well as implantation, without the need for exogenous hormones. It is recommended that prophylactic antibiotics are administered at the time of insertion of the intrauterine device, if the woman has not been screened for sexually transmitted infections.

In all women, the risks of intrauterine contraception include uterine perforation, infection, and displacement of the IUD. It should, therefore, be avoided in women with previous infective endocarditis, and be used with caution in the presence of complicated valvular disease. Intrauterine devices are not recommended in immunosuppressed women, for example those who have undergone heart transplantation, because of the risk of infection.

The levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena ^® ) provides contraceptive protection comparable to that of sterilisation . Most women experience oligomenorrhoea, which is a major advantage in women with cardiac disease, especially in women receiving long-term anticoagulation therapy who may suffer from menorrhagia . Women with pulmonary arterial hypertension may not tolerate a bradycardiac response to cervical instrumentation. So, in these women, LNG-IUS insertion should be carried out in hospital with anaesthetic support. In women with ischaemic heart disease and hyperlipidaemia, the LNG-IUS provides the safest lipid profile, as levels of high-density lipoprotein are increased .

Injectable contraception

Depot medroxyprogesterone acetate (DMPA) is an effective contraceptive injection that has no cardiac contraindications. Good compliance with 12-weekly injections is important for contraceptive effectiveness. Deep intramuscular injections, however, may cause significant haematomas in women receiving anticoagulation therapy. Amenorrhoea is a common side-effect and may be an advantage in women with cyanotic heart disease, many of whom suffer from meDMPAnorrhagia. In women with ischaemic heart disease, there is a small theoretical concern that DMPA may cause a moderately unfavourable alteration in lipid metabolism. In women taking enzyme-inducing drugs such as bosentan, or in women with significantly raised body mass index body mass index, additional supplemental progestogen may be required . Fertility returns to normal within 6 months of cessation of treatment.

Contraceptive implants

Nexplanon ^® is a radio-opaque etonogestrel-releasing implant. It has replaced Implanon ^® and has no cardiac contraindications. Nexplanon ^® is as effective as sterilisation, and produces steadier blood levels and fewer side-effects than injectable contraceptives. The risk of haematoma formation is reduced, as the implant is subdermal and needs replacing every 3 years. The international normalised ratio (INR) should be checked before insertion in women taking warfarin. The efficacy of contraceptive implants is affected by bosentan, so an additional method of contraception should be used to provide reliable contraception for women with pulmonary hypertension.

Emergency hormonal contraception

Women with cardiac disease should be offered emergency contraception if needed. The first choice of oral emergency hormonal contraception is a single dose of 1.5 mg levonorgestrel, taken as a single dose. It should ideally be taken within 12 h of intercourse but no later than 72 h for best effect. An alternative form of emergency contraception, if the woman exceeds the 72-h window, is 30 mg of ulipristal acetate, a selective progesterone receptor modulator, which is licensed for administration up to 120 h after intercourse. Alternatively, a copper IUD may be inserted up to 120 h after intercourse. Insertion, however, carries risks of vagal reaction and infection, as previously discussed. In women who are treated with warfarin, the international INR should also be monitored after emergency oral contraception, as the INR can be affected.

Contraception after cardiac transplant

Over the past 2 decades, the number of successful cardiac transplants and subsequent successful pregnancies has increased. Immunosuppressive agents, such as prednisone, azathioprine, ciclosporin, and tacrolimus are not teratogenic, and so these medications can be continued throughout pregnancy. Mycophenolate mofetil (MMF) is teratogenic and associated with auricular, ocular, and other significant fetal anomalies so MMF is usually switched to azathioprine before conception.

Progestogen-only contraception is suitable for most women after transplant. Low-dosage combined hormonal preparations may be indicated for women who have no additional ongoing cardiac risk factors. Intrauterine devices may pose an infection risk in women taking immunosuppressant treatment, and are best avoided.

In summary, when counselling women with heart disease about the best contraceptive options, the first decision is usually whether oestrogen-containing contraception is safe. If a progestogen-only method is recommended, then the route of delivery needs to be decided. Consideration of whether there is a risk of endocarditis or vagal reaction at insertion of intrauterine contraception, or a risk of haematoma with injectables, will help determine the optimal method of contraception. In addition to safety, the efficacy of the contraceptive method should be considered. The standard progestogen-only contraceptives are safe for women with cardiac disease, but their lower efficacy means they may not be appropriate for women in whom pregnancy carries a high risk.

Drugs used to treat cardiac conditions in the pregnant woman and their effect on the pregnancy

Commonly used cardiovascular drugs that are known teratogens include inhibitors of the renin-angiotensin-aldosterone system (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors [statins]). These drugs should be avoided in pregnancy. Warfarin also crosses the placenta, is teratogenic, and is therefore usually avoided in the first trimester. This is discussed in detail below. Cardioselective and other beta-blockers, vasodilators, and diuretics are all safe in pregnancy .